Medium Chain Acyl CoA Dehydrogenase (MCAD) Deficiency Due to an Exon 8 Duplication in ACADM
2Metabolic Clinic, Pediatric Division, Soroka University Medical Center, Israel
3National Newborn Screening Program, Public Health Services, Ministry of Health, Israel
4Pediatric Neurology Unit and Magen Center for Rare Diseases, Wolfson Medical Center, Israel
5Metabolic Disease Unit, Schneider Children's Medical Center, Israel
6Metabolic Clinic, Ruth Rappaport Children's Hospital, Rambam Medical Center, Israel
7Department of Neonatology, Red Crescent Society Hospital, Israel
8Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel
9Genetics Institute, Tel Aviv Sourasky Medical Center, Israel
10Metabolic Laboratory, Sheba Medical Center, Israel
11Institute of Human Genetics, Galilee Medical Center, Israel
12Medical Genetics Institute, Shaare Zedek Medical Center, Israel
13The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Israel
14Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel-Aviv Sourasky Medical Center, Israel
15Department of Genetics, Hadassah Medical Center, Israel
16Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technolog, Israel
17Sackler School of Medicine, Tel Aviv University, Israel
18Department of Neonatology, Makassed Islamic Hospital, Israel
19Genetics Institute, Kaplan Medical Center, Israel
20Metabolic Service, Department of Pediatrics B and Institute for Rare Diseases, Emek Medical Center, Israel
21School of Medicine, Hebrew University School of Medicine, Israel
22The Azrieli Faculty of Medicine, Bar Ilan, Israel
23The Azrieli Faculty of Medicine, Bar Ilan, Israel
24Faculty of Health Sciences, Ben-Gurion University, Israel
25Pediatric Department, Al-Quds University, Palestinian Authority
26Wilf Children's Hospital, Shaare Zedek Medical Center, Israel
27Institute for Rare Diseases, Soroka University Medical Center, Israel
Introduction: Medium-chain Acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of fatty acid β-oxidation, caused by bi-allelic variants in the ACADM gene. Targeted sequencing of ACADM establishes a molecular diagnosis for most, but not all, patients.
Objective: We sought to establish the molecular basis of MCAD deficiency (MCADD) in a cohort of patients with a biochemical working diagnosis of MCADD, for whom sequencing of ACADM failed to detect bi-allelic pathogenic variants.
Patients and methods: Nineteen newborns with suspected MCADD detected by the Israeli Newborn Screening (NBS) Programme for whom sequencing of the ACADM gene could not establish a molecular diagnosis were subjected to Multiplex Ligation-dependent probe amplification (MLPA) of ACADM, followed by further molecular and biochemical profiling.
Results: A common tandem ACADM exon 8 duplication was detected in 19 (25%) of 77 confirmed MCADD patients identified by newborn screening. The 6052 base pair duplication, flanked by a duplicated MER58A, an aborted transposed element, established the founder North African Jewish decent variant in this cohort. Although highly predicted to be pathogenic, cDNA obtained from a homozygous patient for the duplication, showed both a normal mRNA sequence, as well as a longer aberrant transcript, which might well correlate with the biochemically mild and clinically benign phenotypes.
Conclusion: A likely pathogenic exon 8 duplication in the ACADM gene leading to MCAD deficiency consists of a founder mutation in the North-African Jewish population. We suggest that in patients with a biochemical working diagnosis of MCADD for whom sequencing of ACADM fails to establish a molecular diagnosis, deletion duplication analysis should be considered. Additional studies to expand our understanding of this unique mechanism as well as defining genotype-phenotype correlations are warranted. Nonetheless, such studies could potentially assist in tailoring clinical guidelines for this specific subgroup of MCADD patients.
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